Obesity has been reported to be associated with glomerular injury and ultimate end-stage renal disease (ESRD). Although hypertension or diabetes mellitus in obesity may contribute to the development of ESRD, the molecular mechanisms of obesity-induced renal injury, in particular, the early mechanisms mediating glomerular injury that occur prior to hypertension and diabetes are still poorly understood. In thi grant proposal, we attempt to elucidate an early intracellular molecular mechanism, namely, the Nalp3 inflammasome activation, which may switch on glomerular injury through its inflammatory or non-inflammatory pathway leading to glomerular dysfunction and ultimately sclerosis during obesity. Interestingly, our preliminary studies demonstrated that obesity-induces the Nalp3 inflammasome activation and contributes to the glomerular injury independent of elevated arterial blood pressure and have also shown that beyond inflammation, the activated inflammasomes have direct actions on the podocytes. This may represent a novel pathogenic mechanism of inflammasome activation beyond inflammation. Based on these observations, we hypothesize that obesity increases visfatin production and thereby activates Nalp3 inflammasomes in podocytes to produce IL-1 stimulating inflammatory response in glomeruli and initiating direct podocyte damage, ultimately resulting in glomerular injury and sclerosis. To test this hypothesis, we will first determine whether obesity-induced Nalp3 inflammasome formation and activation contribute to glomerular injury in vivo prior to hypertension in experimental high fat diet (HFD)-induced obesity using Asc-/- mice with or without rescuing Asc gene and wild type mice with and without locally silencing Asc gene. We will then examine how Nalp3 inflammasomes are activated in podocytes with a focus on the role of adipokine visfatin in cultured podocytes and in vivo in mice and to elucidate its functional significance in inflammasome activation. Finally, we will explore the mechanisms by which activated Nalp3 inflammasomes lead to podocyte injury and glomerular dysfunction or sclerosis by studying the actions of inflammasome products such as IL-1, IL-18, pyroptosis and DAMPs in cultured podocytes and in mice with obesity induced by HFD. The findings from the proposed studies will provide new mechanistic insights for targeting inflammasomes to develop novel therapeutic strategies for treatment and prevention of ESRD in obese patients.